Adenosine A3 receptor agonists

ABSTRACT

Disclosed are novel compounds that are A 3  adenosine receptor agonists, useful for treating various disease states, including cancer, cardiac ischemia, leukopenia, and neutropennia.

ADENOSINE A₃ RECEPTOR AGONISTS

[0001] This is a continuation in part of U.S. patent application Ser.No. 10/212,896, filed on Aug. 5, 2002, which claims priority to U.S.Provisional Patent Application Serial No. 60/311,069 filed on Aug. 8,2001 the complete disclosures of which are hereby incorporated byreference.

FIELD OF THE INVENTION

[0002] This invention relates to novel adenosine A₃ receptor agoniststhat are useful in the treatment of neurological, cardiac, and othercellular proliferative disorders. The invention also relates to methodsfor the preparation of such compounds, and to pharmaceuticalcompositions containing them.

BACKGROUND

[0003] Adenosine is a naturally occurring nucleoside, which exerts itsbiological effects by interacting with a family of adenosine receptorsknown as A₁, A_(2a), A_(2b), and A₃, all of which modulate importantphysiological processes. For example, stimulation of the A₁ adenosinereceptors shortens the duration and decreases the amplitude of theaction potential of AV nodal cells, and hence prolongs the refractoryperiod of the AV nodal cell. Thus, stimulation of A₁ receptors providesa method of treating supraventricular tachycardias, includingtermination of nodal re-entrant tachycardias, and control of ventricularrate during atrial fibrillation and flutter. A_(2A) adenosine receptorsmodulate coronary vasodilation, A_(2B) receptors have been implicated inmast cell activation, asthma, vasodilation, regulation of cell growth,intestinal function, and modulation of neurosecretion (See AdenosineA_(2B) Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistovet al., Trends Pharmacol Sci 19:148-153). A₃ adenosine receptorsmodulate cell proliferation processes. In particular, compounds that areA₃ receptor agonists have utility in the therapeutic and/or prophylactictreatment of cancer, cardiac disease, infertility, kidney disease, andCNS disorders. Additionally, A₃ receptor agonists stimulate bone marrowcell proliferation, and thus induce the secretion of G-CSF in the body.Accordingly, A₃ receptor agonists are useful for countering the toxicside effect of drugs, in particular chemotherapeutic drugs, such asleukopenia and neutropenia.

[0004] Few ligands for the A₃ adenosine receptor have been reported.Some non-selective N⁶-substituted adenosine derivatives have beendescribed as agonists for the A₃ receptor, including APNEA(N⁶-2-(4-aminophenyl)ethyladenosine), which has been used successfullyas a radioligand in its iodinated form (Zhou et al.). Typical xanthineand nonxanthine A₁ and A₂ receptor antagonists, however, do not appearto bind to this receptor (Zhou et al.).

[0005] Accordingly, it is desired to provide compounds that are A₃receptor agonists. Preferably, the compounds would be selective for theA₃ receptor, thus avoiding side effects caused by interaction with otheradenosine receptors.

SUMMARY OF THE INVENTION

[0006] It is an object of this invention to provide A₃ receptoragonists. Accordingly, in a first aspect, the invention relates tocompounds of Formula I:

[0007] wherein:

[0008] R¹ is optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl;

[0009] X is a covalent bond or optionally substituted alkylene;

[0010] R² is R⁴-Z-Y—C≡C— or optionally substituted pyrazolyl:

[0011] in which Y is optionally substituted alkylene, Z is oxygen,sulfur or —NH—, and R⁴ is optionally substituted aryl or optionallysubstituted heteroaryl; and

[0012] R³ is hydroxymethyl or —C(O)—NR⁵R⁶;

[0013] in which R⁵ and R⁶ are independently hydrogen or lower alkyl;

[0014] and the pharmaceutically acceptable salts, esters and prodrugsthereof.

[0015] A second aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of acompound of Formula I and at least one pharmaceutically acceptableexcipient.

[0016] A third aspect of this invention relates to a method of using thecompounds of Formula I in the treatment of a disease or condition in amammal that can be usefully treated with an A₃ receptor agonist,comprising administering to a mammal in need thereof a therapeuticallyeffective dose of a compound of Formula I. Such diseases include, butare not limited to, cancer, renal and cardiac ischemia,neurodegenerative disorders, infertility, neutropenia, kidney disease,and CNS disorders.

[0017] A fourth aspect of this invention relates to methods of preparingthe compounds of Formula I.

[0018] Of the compounds of Formula I, one preferred class includes thosein which R² is optionally substituted pyrazol-1-yl, especially where R¹is optionally substituted alkyl or optionally substituted aryl, R³ ishydroxymethyl, and X is a covalent bond. Of these compounds, onepreferred group includes those compounds in which R² is pyrazol-1-ylsubstituted by optionally substituted lower alkyl, ester, aminocarbonyl,optionally substituted aryl, or optionally substituted heteroaryl.

[0019] A preferred subgroup includes those compounds in which R² ispyrazol-1-yl substituted by optionally substituted phenyl or optionallysubstituted alkyl, and R¹ is optionally substituted alkyl. Morepreferred are those compounds in which R¹ is lower alkyl of 1-3 carbonatoms and R² is pyrazol-1-yl substituted by phenyl or benzyl havingmethoxy or chloro substitutions.

[0020] A second preferred subgroup includes those compounds in which R²is pyrazol-1-yl substituted by optionally substituted heteroaryl and R¹is optionally substituted alkyl. More preferred are those compounds inwhich R¹ is lower alkyl of 1-3 carbon atoms and R² is pyrazol-1-ylsubstituted by pyridine.

[0021] A third preferred subgroup includes those compounds in which R²is pyrazol-1-yl substituted by optionally substituted phenyl, R¹ isoptionally substituted phenyl, and X is alkylene. More preferred arethose compounds in which R¹ is 3-iodophenyl, especially where X ismethylene.

[0022] A second preferred class includes compounds in which R² ispyrazol-4-yl optionally substituted by optionally substituted phenyl oroptionally substituted alkyl, especially where R¹ is optionallysubstituted alkyl and X is a covalent bond. More preferred are thosecompounds in which R¹ is lower alkyl.

[0023] A third preferred class includes those compounds in which R² isR⁴-Z-Y—C≡C—, especially where R⁴ is optionally substituted phenyl and Yis alkylene of 1, 2, or 3 carbon atoms. Of these compounds, a preferredgroup includes those compounds in which R⁴ is phenyl optionallysubstituted by methoxy or chloro, and Y is methylene, R¹ is optionallysubstituted lower alkyl, R³ is hydroxy, X is a covalent bond, and Z isoxygen.

[0024] Definitions and General Parameters

[0025] As used in the present specification, the following words andphrases are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

[0026] The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl,n-decyl, tetradecyl, and the like.

[0027] The term “substituted alkyl” refers to:

[0028] 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

[0029] 2) an alkyl group as defined above that is interrupted by 1-10atoms independently chosen from oxygen, sulfur and NR_(a)—, where R_(a)is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano, or —S(O)_(n)R, in which R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2; or

[0030] 3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5substituents as defined above and is also interrupted by 1-10 atoms asdefined above.

[0031] The term “lower alkyl” refers to a monoradical branched orunbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and thelike.

[0032] The term “substituted lower alkyl” refers to lower alkyl asdefined above having 1 to 5 substituents, preferably 1, 2, or 3substituents, as defined for substituted alkyl, or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4, or 5 atoms asdefined for substituted alkyl, or a lower alkyl group as defined abovethat has both 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4, or 5 atoms as defined above.

[0033] The term “alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1 to 20carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4,5 or 6 carbon atoms. This term is exemplified by groups such asmethylene (—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g.,—CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

[0034] The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1, 2, 3,4, 5, or 6 carbon atoms.

[0035] The term “substituted alkylene” refers to:

[0036] (1) an alkylene group as defined above having 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

[0037] (2) an alkylene group as defined above that is interrupted by1-20 atoms independently chosen from oxygen, sulfur and NR_(a)—, whereR_(a) is chosen from hydrogen, optionally substituted alkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected fromcarbonyl, carboxyester, carboxyamide and sulfonyl; or

[0038] (3) an alkylene group as defined above that has both 1, 2, 3, 4or 5 substituents as defined above and is also interrupted by 1-20 atomsas defined above. Examples of substituted alkylenes are chloromethylene(—CH(Cl)—), aminoethylene (—CH(NH₂)CH₂—), methylaminoethylene(—CH(NHMe)CH₂—), 2-carboxypropylene isomers(—CH₂CH(CO₂H)CH₂—),ethoxyethyl (—CH₂CH₂O—CH₂CH₂—), ethylmethylaminoethyl(—CH₂CH₂N(CH₃)CH₂CH₂—),1-ethoxy-2-(2-ethoxy-ethoxy)ethane(—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

[0039] The term “aralkyl” refers to an aryl group covalently linked toan alkylene group, where aryl and alkylene are defined herein.“Optionally substituted aralkyl” refers to an optionally substitutedaryl group covalently linked to an optionally substituted alkylenegroup. Such aralkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

[0040] The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y-Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups are alkyl-O—and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

[0041] The term “alkylthio” refers to the group R—S—, where R is asdefined for alkoxy.

[0042] The term “alkenyl” refers to a monoradical of a branched orunbranched unsaturated hydrocarbon group preferably having from 2 to 20carbon atoms, more preferably 2 to 10 carbon atoms and even morepreferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond(vinyl). Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂),1-propylene or allyl (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

[0043] The term “lower alkenyl” refers to alkenyl as defined abovehaving from 2 to 6 carbon atoms.

[0044] The term “substituted alkenyl” refers to an alkenyl group asdefined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2,or 3 substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0045] The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or propynyl, —C≡CCH₃), and the like. In the eventthat alkynyl is attached to nitrogen, the triple bond cannot be alpha tothe nitrogen.

[0046] The term “substituted alkynyl” refers to an alkynyl group asdefined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2,or 3 substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0047] The term “aminocarbonyl” refers to the group —C(O)NRR where eachR is independently hydrogen, alkyl, cycloaklyl, aryl, heteroaryl,heterocyclyl or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

[0048] The term “ester” or “carboxyester” refers to the group —C(O)OR,where R is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, whichmay be optionally further substituted by alkyl, alkoxy, halogen, CF₃,amino, substituted amino, cyano, or —S(O)_(n)R_(a), in which R_(a) isalkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0049] The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Allsubstituents may be optionally further substituted by alkyl, alkoxy,halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, in which Ris alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0050] The term “acyloxy” refers to the groups —O(O)C-alkyl,—O(O)C-cycloalkyl, —O(O)C-aryl, —O(O)C-heteroaryl, and—O(O)C-heterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0051] The term “aryl” refers to an aromatic carbocyclic group of 6 to20 carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like.

[0052] Unless otherwise constrained by the definition for the arylsubstituent, such aryl groups can optionally be substituted with 1, 2,3, 4 or 5 substituents, preferably 1, 2, or 3 substituents, selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

[0053] The term “aryloxy” refers to the group aryl-O— wherein the arylgroup is as defined above, and includes optionally substituted arylgroups as also defined above. The term “arylthio” refers to the groupR—S—, where R is as defined for aryl.

[0054] The term “amino” refers to the group —NH₂.

[0055] The term “substituted amino” refers to the group —NRR where eachR is independently selected from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl provided that bothR groups are not hydrogen, or a group —Y-Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

[0056] The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0057] The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to20 carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, andbicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an arylgroup, for example indan, and the like.

[0058] The term “substituted cycloalkyl” refers to cycloalkyl groupshaving 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0059] The term “halogen” or “halo” refers to fluoro, bromo, chloro, andiodo.

[0060] The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

[0061] The term “heteroaryl” refers to an aromatic group (i.e.,unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatomsselected from oxygen, nitrogen and sulfur within at least one ring.

[0062] Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1, 2, or 3 substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl (an alkyl ester), arylthio, heteroaryl,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,aralkyl, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl)or multiple condensed rings (e.g., indolizinyl, benzothiazole, orbenzothienyl). Examples of nitrogen heterocycles and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

[0063] One choice for the definition of R⁴ in Formula I is a heteroaryl,namely an optionally substituted pyrazole. This definition is intendedto include pyrazoles attached:

[0064] a) through the N1 position of the pyrazole, that is apyrazol-1-yl moiety of the formula:

[0065] in which A represents the point of attachment to the 2-positionof the compound of Formula I, and R⁵, R⁶, and R⁷ are independentlyhydrogen or those optional substitutions shown for heteroaryl above; and

[0066] b) through any carbon atom of the pyrazole, that is a C-pyrazolylof the formula:

[0067] in which A represents the point of attachment to the 2-positionof the compound of Formula I, and R⁸, R⁹ and, R¹⁰ are independentlyhydrogen or those optional substitutions shown for heteroaryl above.

[0068] Preferred are optionally substituted pyrazol-1-yl and optionallysubstituted pyrazol-4-yl. Preferred substitutions are hydrogen,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, and optionally substituted heteroaralkyl.

[0069] The term “heteroaryloxy” refers to the group heteroaryl-O—.

[0070] The term “heterocyclyl” refers to a monoradical saturated orpartially unsaturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

[0071] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1 to 5, and preferably 1, 2, or 3 substituents,selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a singlering or multiple condensed rings. Preferred heterocyclics includetetrahydrofuranyl, morpholino, piperidinyl, and the like.

[0072] The term “thiol” refers to the group —SH.

[0073] The term “substituted alkylthio” refers to the group—S-substituted alkyl.

[0074] The term “heteroarylthiol” refers to the group —S-heteroarylwherein the heteroaryl group is as defined above including optionallysubstituted heteroaryl groups as also defined above.

[0075] The term “sulfoxide” refers to a group —S(O)R, in which R isalkyl, aryl, or heteroaryl. “Substituted sulfoxide” refers to a group—S(O)R, in which R is substituted alkyl, substituted aryl, orsubstituted heteroaryl, as defined herein.

[0076] The term “sulfone” refers to a group —S(O)₂R, in which R isalkyl, aryl, or heteroaryl. “Substituted sulfone” refers to a group—S(O)₂R, in which R is substituted alkyl, substituted aryl, orsubstituted heteroaryl, as defined herein.

[0077] The term “keto” refers to a group —C(O)—. The term “thiocarbonyl”refers to a group —C(S)—. The term “carboxy” refers to a group —C(O)—OH.

[0078] “Optional” or “optionally” means that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where said event or circumstance occurs and instancesin which it does not.

[0079] The term “compound of Formula I” is intended to encompass thecompounds of the invention as disclosed, and the pharmaceuticallyacceptable salts, pharmaceutically acceptable esters, and prodrugs ofsuch compounds.

[0080] The term “therapeutically effective amount” refers to that amountof a compound of Formula I that is sufficient to effect treatment, asdefined below, when administered to a mammal in need of such treatment.The therapeutically effective amount will vary depending upon thesubject and disease condition being treated, the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

[0081] The term “treatment” or “treating” means any treatment of adisease in a mammal, including:

[0082] (i) preventing the disease, that is, causing the clinicalsymptoms of the disease not to develop;

[0083] (ii) inhibiting the disease, that is, arresting the developmentof clinical symptoms; and/or

[0084] (iii) relieving the disease, that is, causing the regression ofclinical symptoms.

[0085] In many cases, the compounds of this invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

[0086] Specific examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

[0087] Pharmaceutically acceptable acid addition salts may be preparedfrom inorganic and organic acids. Salts derived from inorganic acidsinclude hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

[0088] As used herein, “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

Nomenclature

[0089] The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I in which R¹ ismethyl, R² is 4-(4-methoxyphenyl)pyrazol-1-yl, R³ is hydroxymethyl, andX is a covalent bond:

[0090] which is named:

[0091](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol

Synthesis of the Compounds of Formula I

[0092] An example of a method for preparing the compounds of Formula Iwhere R² is optionally substituted pyrazol-1-yl is shown in ReactionScheme I.

[0093] where Ac is acetyl, and X is a covalent bond or optionallysubstituted alkylene.

[0094] Step 1—Preparation of Formula (2)

[0095] The compound of formula (2) is prepared by displacement of the6-chloro of a compound of formula (1), which is prepared as described inJ. F. Gorster and R. K. Robins, J. Org. Chem. 1966, Vol. 31, 3258-62.The compound of formula (1) is reacted with a compound of formulaR¹XNH₂, where X is a covalent bond or optionally substituted alkylene,in the presence of a base. The reaction is carried out in an inertprotic solvent, for example methanol, ethanol, n-butanol, and the like,at a temperature of between room temperature and about reflux, for about12-48 hours. When the reaction is substantially complete, the product offormula (2) is isolated by conventional means, for example by removal ofthe solvent under reduced pressure, followed by chromatography of theresidue on silica gel.

[0096] Step 2—Preparation of Formula (3)

[0097] The compound of formula (2) is converted to a compound of formula(3) by reaction with hydrazine hydrate. The reaction is carried out withno solvent, or optionally in a protic solvent, for example ethanol, at atemperature of between room temperature and about reflux, for about12-48 hours. When the reaction is substantially complete, the product offormula (3) is isolated by conventional means, for example by removal ofsolvent under reduced pressure and triturating the product with ether.Alternatively, the compound of Formula (3) is used in the next stepwithout purification.

[0098] Step 3—Preparation of Formula I

[0099] The compound of formula (3) is converted to a compound of FormulaI by reaction with an optionally substituted 1,3-propanedione derivativeof formula (4). The reaction is carried out by suspending the compoundof formula (3) in a protic solvent, preferably ethanol, adding thecompound of formula (4), and refluxing the mixture for about 2-16 hours.When the reaction is substantially complete, the product of Formula I isisolated by conventional means, for example filtering off the product.

[0100] For example, starting with a compound of formula (4) in which R⁵and R⁷ are hydrogen and R⁶ is 4-methoxyphenyl provides a compound ofFormula I in which R² is 4-methoxyphenylpyrazol-1-yl. Starting with acompound of formula (4) in which R⁵ and R⁷ are hydrogen and R⁶ is —CO₂Etprovides a compound of Formula I in which R² is4-ethoxycarbonylpyrazol-1-yl. This ester group can then be hydrolyzedunder basic conditions to give the free acid, which in turn can beconverted to acid derivatives such as optionally substituted amide bymeans well known to those skilled in the art, or by the method shown inReaction Scheme IA.

[0101] Step 1—Protection of the Compound of Formula I where R⁶ isEthoxycarbonyl

[0102] The compound of Formula I in which R⁶ is ethoxycarbonyl isdissolved in a polar solvent, preferably DMF, and imidazole and tertiarybutyldimethylsilyl chloride added. The reaction is carried out at atemperature of 50-100° C., for about 12-48 hours. When the reaction issubstantially complete, the product is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby flash chromatography of the residue on silica gel.

[0103] Step 2—Hydrolysis of the Ethyl Ester to the Carboxylic Acid

[0104] The product from Step 1 is suspended in a mixture of water, analcohol, and a strong base, preferably potassium hydroxide in methanol.The reaction is carried out at a temperature of 0-40° C., preferablyabout 25° C., for about 2-5 days, preferably about 3 days. When thereaction is substantially complete, the solvent is removed under reducedpressure, the residue acidified to a pH of about 5, and the product isisolated by conventional means, for example by filtration.

[0105] Step 3—Preparation of an Amide

[0106] The product from Step 2 is dissolved in an inert solvent,preferably dichloromethane, to which is added HBTU, HOBt,N-methylmorpholine,a catalytic amount of DMAP, and an optionallysubstituted amine of formula HNRR, as defined above. The reaction iscarried out at a temperature of 0-40° C., preferably about 25° C., forabout 8-48 hours, preferably about 24 hours. When the reaction issubstantially complete, the product is isolated by conventional means.

[0107] Step 4—Deprotection

[0108] The product from Step 2 is treated with a solution of ammoniumfluoride in methanol. The reaction is carried out at a temperature ofabout reflux, for about 8-48 hours, preferably about 24 hours. When thereaction is substantially complete, the solvent is removed under reducedpressure, the residue acidified to a pH of about 5, and the product isisolated by conventional means, for example by preparative TLC.

[0109] A example of a method for preparing the compounds of Formula Iwhere R² is optionally substituted pyrazol-4-yl is shown in ReactionScheme II. This method and other general methods of preparation ofpyrazol-4-yl derivatives are shown in U.S. Pat. No. 6,214,807, thecomplete disclosure of which is hereby incorporated by reference.

[0110] The starting material of formula (5) is prepared by means wellknow in the art. The intermediate of formula (9) is prepared as shownbelow.

[0111] Condensation of a 1,3-dione of formula (a) with hydrazine in anappropriate solvent provides a pyrazole of formula (b), which isN-alkylated with an appropriate halide of formula R⁸Hal to give acompound of formula (c). Formation of an anion at the 4-position with astrong base followed by quenching with iodine provides the 4-iododerivative of formula (9) (F. Effenberger et. al. J. Org. Chem. (1984),49, 4687).

[0112] The iodopyrazole of formula (9) is converted to the correspondingcompound of formula (10) by palladium mediated coupling with thecompound of formula (8) in the presence or absence of copper salts (K.Kato et. al. J. Org. Chem. 1997, 62, 6833-6841; Palladium Reagents andCatalysts-Innovations in Organic Synthesis, Tsuji, John Wiley and Sons,1995). The synthesis of the tributyltin derivative of formula (7) hasbeen previously described (K. Kato et. al. J. Org. Chem. 1997, 62,6833-6841), as shown above in Reaction Scheme II.

[0113] An example of a method for preparing the compounds of Formula Iwhere R² is an ethynyl derivative is shown in Reaction Scheme III.

[0114] where R⁸ represents optionally substituted aryl or aralkyl and Zis oxygen, sulfur, or —NH—.

[0115] Step 1—Preparation of Formula (12)

[0116] The starting compound of formula (11) (2-iodoadenosine) isprepared in four steps from guanosine following literature procedures(M. J. Robins et.al. Can. J. Chem. (1981), 59, 2601-2607; J. F. Cersteret.al. Org. Synthesis, 242-243; V. Nair at. al., J. Org. Chem., (1988),53, 3051-3057).

[0117] The compound of formula (12) is prepared by displacement of the6-chloro substituent of a compound of formula (11) by reaction with acompound of formula R¹XNH₂, where X is a covalent bond or optionallysubstituted alkylene, in the presence of a base, in the same manner asshown above for the preparation of a compound of formula (2).

[0118] Step 2—Preparation of Formula I

[0119] The compound of Formula I where R² is an ethynyl derivative isprepared from a compound of formula (12) by reaction with anappropriately substituted ethynyl derivative of formula (13). Thereaction is carried out in a polar solvent, preferably DMF, in thepresence of copper iodide anddichlorobis(triphenylphosphine)palladium(II) catalyst, at a temperatureof about 50-100° C., preferably in a sealed tube, for about 2-16 hours.When the reaction is substantially complete, the product of Formula I isisolated by conventional means, for example by thin layerchromatography.

Preferred Processes and Last Steps

[0120] The compounds of the present invention can be prepared accordingto the following last steps:

[0121] 1. Contacting a compound of the formula:

[0122] with a compound of formula:

[0123] 2. Contacting a compound of the formula:

[0124] with a compound of the formula:

[0125] and contacting the product with a mild acid, for example ammoniumfluoride, to remove the protecting groups.

[0126] 3. Contacting a compound of the formula:

[0127] with a compound of the formula:

[0128] in the presence of a copper salt and a catalyst.

Utility, Testing and Administration

[0129] General Utility

[0130] The compounds of Formula I are effective in the treatment ofconditions known to respond to administration of A₃ adenosine receptoragonists. Such conditions include, but are not limited to, modulation ofcell proliferation processes. In particular, compounds that are A₃receptor agonists have utility in the therapeutic and/or prophylactictreatment of cancer, cardiac disease (including use as anischemia-reperfusion agent), infertility, kidney disease, and CNSdisorders. Additionally, they are useful for countering the toxic sideeffect of drugs, in particular chemotherapeutic drugs, such asleukopenia and neutropenia.

[0131] Testing

[0132] Activity testing is conducted as described in those patents andpatent applications referenced above, and in the Examples below, and bymethods apparent to one skilled in the art.

[0133] Pharmaceutical Compositions

[0134] The compounds of Formula I are usually administered in the formof pharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed.(G. S. Banker & C. T. Rhodes, Eds.).

[0135] Administration

[0136] The compounds of Formula I may be administered in either singleor multiple doses by any of the accepted modes of administration ofagents having similar utilities, for example as described in thosepatents and patent applications incorporated by reference, includingrectal, buccal, intranasal and transdermal routes, by intra-arterialinjection, intravenously, intraperitoneally, parenterally,intramuscularly, subcutaneously, orally, topically, as an inhalant, orvia an impregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer.

[0137] One mode for administration is parental, particularly byinjection. The forms in which the novel compositions of the presentinvention may be incorporated for administration by injection includeaqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.Aqueous solutions in saline are also conventionally used for injection,but less preferred in the context of the present invention. Ethanol,glycerol, propylene glycol, liquid polyethylene glycol, and the like(and suitable mixtures thereof), cyclodextrin derivatives, and vegetableoils may also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like.

[0138] Sterile injectable solutions are prepared by incorporating thecompound of Formula I in the required amount in the appropriate solventwith various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

[0139] Oral administration is another route for administration of thecompounds of Formula I. Administration may be via capsule or entericcoated tablets, or the like. In making the pharmaceutical compositionsthat include at least one compound of Formula I, the active ingredientis usually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, it can be a solid, semi-solid,or liquid material (as above), which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, sterileinjectable solutions, and sterile packaged powders.

[0140] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents.

[0141] The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart. Controlled release drug delivery systems for oral administrationinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examplesof controlled release systems are given in U.S. Pat. Nos. 3,845,770;4,326,525; 4,902514; and 5,616,345. Another formulation for use in themethods of the present invention employs transdermal delivery devices(“patches”). Such transdermal patches may be used to provide continuousor discontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

[0142] The compositions are preferably formulated in a unit dosage form.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).The compounds of Formula I are effective over a wide dosage range andare generally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 10mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg,and for parenteral administration, preferably from 10 to 700 mg of acompound of Formula I, more preferably about 50-200 mg. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

[0143] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

[0144] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

[0145] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

[0146] The following examples are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventor to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLE 1 Preparation of a Compound of Formula (2)

[0147] A. Preparation of a Compound of Formula (2) Where R¹ is Methyland X is a Covalent Bond

[0148]3,4-diacetyloxy-2-(2,6-dichloropurin-9-yl)-5-(2-oxopropoxy)tetrahydrofuran,the compound of formula (1) (1 mmol), was suspended in a mixture of 1:4methylamine/MeOH, and the mixture stirred at room temperature for 24hours. The solvent was removed under reduced pressure and the residuetriturated in ether, to afford(4S,2R,3R,5R)-2-[2-chloro-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol,a compound of formula (2) as a white solid.

[0149] B. Preparation of a Compound of Formula (2), varying R¹ and X

[0150] Similarly, following the procedure of 1A above, but replacingmethylamine by propylamine and 3-iodobenzylamine, the followingcompounds of formula (2) were prepared:

[0151](4S,2R,3R,5R)-2-[2-chloro-6-(propylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;and

[0152](4S,2R,3R,5R)-2-[2-chloro-6-(3-iodobenzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol.

[0153] C. Preparation of a Compound of Formula (2), Varying R¹ and X

[0154] Similarly, following the procedure of 1A above, but replacingmethylamine by other compounds of formula R¹XNH₂, the followingcompounds of formula (2) are prepared:

[0155](4S,2R,3R,5R)-2-[2-chloro-6-(ethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0156](4S,2R,3R,5R)-2-[2-chloro-6-(n-propylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0157](4S,2R,3R,5R)-2-[2-chloro-6-(cyclopropylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0158](4S,2R,3R,5R)-2-[2-chloro-6-(cyclopropylmethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0159](4S,2R,3R,5R)-2-[2-chloro-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0160](4S,2R,3R,5R)-2-[2-chloro-6-(anilinopurin-9-yl)]-5-(hydroxymethyl)oxolane-3,4-diol;

[0161](4S,2R,3R,5R)-2-[2-chloro-6-(4-chlorobenzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0162](4S,2R,3R,5R)-2-[2-chloro-6-(benzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0163](4S,2R,3R,5R)-2-[2-chloro-6-(2-fluorobenzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0164](4S,2R,3R,5R)-2-[2-chloro-6-(pyrid-2-ylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;and

[0165](4S,2R,3R,5R)-2-[2-chloro-6-(pyrrol-3-ylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol.

[0166] D. Preparation of a Compound of Formula (2), Varying R¹ and X

[0167] Similarly, following the procedure of 1A above, but replacingmethylamine by other compounds of formula R¹XNH₂, other compounds offormula (2) are prepared.

EXAMPLE 2 Preparation of a Compound of Formula (3)

[0168] A. Preparation of a Compound of Formula (3) Where R¹ is Methyland X is a Covalent Bond

[0169](4S,2R,3R,5R)-2-[2-chloro-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol,a compound of formula (2) (0.5 mmol), was suspended in hydrazine hydrate(5 mL), and the mixture was allowed to stir at room temperature for 24hours. The hydrazine was removed under reduced pressure and the residuetriturated with ether and filtered, to afford(4S,2R,3R,5R)-2-[2-hydrazino-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol,a compound of formula (3), as a white solid.

[0170] B. Preparation of a Compound of Formula (3), Varying R¹ and X

[0171] Similarly, following the procedure of 2A above, but replacing2-(2-chloro-6-methylaminopurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diolby the propylamino and 3-iodobenzylamino anaolgs of formula (2), thefollowing compounds of formula (3) were prepared:

[0172](4S,2R,3R,5R)-2-[2-hydrazino-6-(n-propylamino)purin-9-yl]-5-(hydroxylethyl)oxolane-3,4-diol;and

[0173](4S,2R,3R,5R)-2-[2-hydrazino-6-(3-iodobenzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol.

[0174] C. Preparation of a Compound of Formula (3), Varying R¹ and X

[0175] Similarly, following the procedure of 2A above, but replacing2-(2-chloro-6-methylaminopurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diolby other compounds of formula (2), the following compounds of formula(3) are prepared:

[0176](4S,2R,3R,5R)-2-[2-hydrazino-6-(ethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0177](4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopropylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0178](4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopropylmethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0179](4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0180](4S,2R,3R,5R)-2-[2-hydrazino-6-(anilinopurin-9-yl)]-5-(hydroxymethyl)oxolane-3,4-diol;

[0181](4S,2R,3R,5R)-2-[2-hydrazino-6-(4-chlorobenzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0182](4S,2R,3R,5R)-2-[2-hydrazino-6-(benzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0183](4S,2R,3R,5R)-2-[2-hydrazino-6-(2-fluorobenzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;

[0184](4S,2R,3R,5R)-2-[2-hydrazino-6-(pyrid-2-ylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol;and

[0185](4S,2R,3R,5R)-2-[2-hydrazino-6-(pyrrol-3-ylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol.

[0186] D. Preparation of a Compound of Formula (3), Varying R¹ and X

[0187] Similarly, following the procedure of 2A above, but replacing2-(2-chloro-6-methylaminopurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diolby other compounds of formula (2), other compounds of formula (3) areprepared.

EXAMPLE 3 Preparation of a Compound of Formula I

[0188] A. Preparation of a Compound of Formula I Where R¹ is Methyl, R²is 4-(4-Methoxyphenyl)pyrazol-1-yl, and X is a Covalent Bond

[0189](4S,2R,3R,5R)-2-[2-hydrazino-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol(0.5 mmol) was suspended in 3 mL of ethanol and to the suspension wasadded 2-(4-methoxyphenyl)malonaldehyde, a compound of formula (4). Themixture was heated at reflux for 5 hours, and the precipitate thusformed was collected by filtration, and washed with ethanol and ether toafford(4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol,a compound of Formula I, Ms, 455.43 (M+1).

[0190] B. Preparation of a Compound of Formula I, varying R¹, R², and X

[0191] Similarly, following the procedure of 3A above, but optionallyreplacing2-(2-hydrazino-6-methylaminopurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diolwith other compounds of formula (3), and optionally replacing2-(4-methoxyphenyl)malonaldehyde with other compounds of formula (4),the following compounds of Formula I were prepared:

[0192](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-ethoxycarbonyl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0193](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-ethoxycarbonyl)pyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol;

[0194](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-ethoxycarbonyl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0195](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(3-ethoxycarbonyl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0196](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-ethoxycarbonyl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0197](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(3-ethoxycarbonyl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0198](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(amido)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0199](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(methylamido)pyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol;

[0200](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(ethylamido)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0201](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(propylamido)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0202](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(cyclopentylamido)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0203](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(ethylamido)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0204](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methylphenyl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0205](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methylphenyl)pyrazolyl]-6-(cyclopentylamino)purin-9-yl}oxolane-3,4-diol;

[0206](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol;

[0207](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0208](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-chlorophenyl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0209](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyrimidin-5-yl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0210](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyrimidin-5-yl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0211](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyridin-2-yl)pyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol;

[0212](4S,2R,3R,5R)-5-(hydroxylethyl)-2-[4-(pyridin-2-yl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0213](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyridin-4-yl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0214](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyridin-4-yl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0215](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyridin-2-yl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0216](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(benzoxazol-2-yl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0217](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(benzoxazol-2-yl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0218](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyridin-2-yl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0219](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(quinolin-2-yl)pyrazolyl]-6-(3-methylamino)purin-9-yl}oxolane-3,4-diol;

[0220](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(isoquinolin-1-yl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0221](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[3,5-dimethylpyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0222](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-n-butyl-3,5-dimethylpyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;and

[0223](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-n-propyl-3,5-dimethylpyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol.

[0224] C. Preparation of a Compound of Formula I, Varying R¹, R², and X

[0225] Similarly, following the procedure of 3A above, but optionallyreplacing2-(2-hydrazino-6-methylaminopurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diolwith other compounds of formula (3), and optionally replacing2-(4-methoxyphenyl)malonaldehyde with other compounds of formula (4),the following compounds of Formula I are prepared:

[0226](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(ethylamino)purin-9-yl}oxolane-3,4-diol;

[0227](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-ethoxycarbonyl)pyrazolyl]-6-(ethylamino)purin-9-yl}oxolane-3,4-diol;

[0228](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol;

[0229](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(cyclopropylamino)purin-9-yl}oxolane-3,4-diol;

[0230](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(cyclopropylmethylamino)purin-9-yl}oxolane-3,4-diol;

[0231](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-propylamido)pyrazolyl]-6-(cyclopropylamino)purin-9-yl}oxolane-3,4-diol;

[0232](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(anilinopurin-9-yl}oxolane-3,4-diol;

[0233](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[pyridin-4-yll)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0234](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(benzylamino)purin-9-yl}oxolane-3,4-diol;

[0235](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(2-fluorobenzylamino)purin-9-yl}oxolane-3,4-diol;

[0236](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(pyrid-2-ylamino)purin-9-yl}oxolane-3,4-diol;and

[0237](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(pyrrol-3-ylmethylamino)purin-9-yl}oxolane-3,4-diol.

[0238] D. Preparation of a Compound of Formula I, Varying R¹ R², and X

[0239] Similarly, following the procedure of 3A above, but optionallyreplacing2-(2-hydrazino-6-methylaminopurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diolwith other compounds of formula (3), and optionally replacing2-(4-methoxyphenyl)malonaldehyde with other compounds of formula (4),other compounds of Formula I are prepared:

EXAMPLE 4 Preparation of a Compound of Formula (12)

[0240] A. Preparation of a Compound of Formula (12) Where R¹ is Methyl

[0241] A mixture of 40% aqueous methylamine (1 mL) and 2-iodoadenosine(100 mg) in methanol (2 mL) was stirred at room temperature for 12hours. The precipitate was filtered off, washed with ether and driedunder vacuum to afford 2-iodo-6-methylamino adenosine, a compound offormula (11).

[0242] B. Preparation of a Compound of Formula (12), Varying R¹

[0243] Similarly, following the procedure of 4A above, but replacingmethylamine with other amines of formula RINH₂, the following compoundsof formula (11) were prepared:

[0244] 2-iodo-6-n-propylamino adenosine; and

[0245] 2-iodo-6-(3-iodobenzyl)amino adenosine.

[0246] C. Preparation of a Compound of Formula (12), Varying R¹

[0247] Similarly, following the procedure of 4A above, but replacingmethylamine with other amines of formula HNRR, the following compoundsof formula (11) are prepared:

[0248] 2-iodo-6-ethylamino adenosine;

[0249] 2-iodo-6-isopropylamino adenosine;

[0250] 2-iodo-6-n-hexylamino adenosine;

[0251] 2-iodo-6-cyclopropylamino adenosine;

[0252] 2-iodo-6-cyclopentylamino adenosine;

[0253] 2-iodo-6-(3-hydroxycyclopentyl)amino adenosine;

[0254] 2-iodo-6-cyclopentylmethylamino adenosine;

[0255] 2-iodo-6-phenylamino adenosine;

[0256] 2-iodo-6-benzylamino adenosine;

[0257] 2-iodo-6-(4-methoxybenzyl)amino adenosine;

[0258] 2-iodo-6-(4-fluorobenzyl)amino adenosine;

[0259] 2-iodo-6-(pyridy-3-yl)amino adenosine; and

[0260] 2-iodo-6-(furan-2-yl)amino adenosine.

[0261] D. Preparation of a Compound of Formula (12), Varying R¹

[0262] Similarly, following the procedure of 4A above, but replacingmethylamine with other amines of formula HNRR, other compounds offormula (11) are prepared.

EXAMPLE 5 Preparation of a Compound of Formula I

[0263] A. Preparation of a Compound of Formula I Where R¹ is Methyl, R²is 3-phenoxypropyn-1-yl, and R⁸ is Phenyl

[0264] To a solution of 2-iodo-6-methylamino adenosine (50 mg) andprop-2-ynyloxybenzene (0.022 mL, 0.16 mmol) in N,N-dimethylformamide (1ml) and triethylamine (0.021 mL, 0.16 mmol) at 23 C was added copperiodide (5 mg, 0.026 mmol) anddichlorobis-(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol)catalyst. After being stirred in a sealed reaction-vial at 80° C. for 6hours, the reaction was concentrated in vacuo, and the residue purifiedby preparatory thin layer chromatography (methylene chloride:methanol9:1) to afford(4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(methylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol,a compound of Formula I. MS: 412.1 (M+1).

[0265] B. Preparation of a Compound of Formula I, varying R²

[0266] Similarly, following the procedure of 5A above, but replacingprop-2-ynyloxybenzene with other compounds of formula (7), the followingcompounds of Formula I were prepared:

[0267](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[2-(3-hydroxy-3-phenylprop-1-ynyl)-6-(methylamino)purin-9-yl]oxolane-3,4-diol;

[0268](4S,2R,3R,5R)-2-{2-[3-(4-chlorophenoxy)prop-1-ynyl]-6-(methylamino)purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol;and

[0269](4S,2R,3R,5R)-2-{2-[3-(2-methoxyphenoxy)prop-1-ynyl]-6-(methylamino)purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol.

[0270] C. Preparation of a Compound of Formula I, Varying R¹, R², and X

[0271] Similarly, following the procedure of 5A above, but replacingprop-2-ynyloxybenzene with other compounds of formula (7), the followingcompounds of Formula I are prepared:

[0272](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(ethylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0273](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(n-propylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0274](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(isopropylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0275](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(n-hexylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0276](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(cyclopropylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0277](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(cyclopentylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0278](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(3-hydroxycyclopentylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0279](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(cyclopentylmethylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0280](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(phenylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0281](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(benzylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0282](4S,2R,3R,1R)-5-(hydroxymethyl)-2-[6-(4-methoxybenzylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0283](4S,2R,3R,1R)-5-(hydroxymethyl)-2-[6-(4-fluorobenzylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;

[0284](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(pyrid-3-ylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol;and

[0285](4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(furan-2-ylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol.

[0286] D. Preparation of a Compound of Formula I, Varying R¹, R², and X

[0287] Similarly, following the procedure of 5A above, but replacingprop-2-ynyloxybenzene with other compounds of formula (7), othercompounds of Formula I are prepared.

EXAMPLE 6

[0288] Following the procedures shown in Reaction Scheme II above, asdetailed in U.S. Pat. No. 6,214,807, the following compounds of FormulaI in which R² is an optionally substituted C-pyrazole were made:

[0289](1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl}pyrazol-4-yl)-N-(4-chlorophenyl)carboxamide;

[0290](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[1-benzylpyrazol-4-yl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol;

[0291](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[1-benzylpyrazol-4-yl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol;

[0292](4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[1-benzylpyrazol-4-yl]-6-(3-iodophenylamino)purin-9-yl}oxolane-3,4-diol;

[0293] The following examples illustrate the preparation ofrepresentative pharmaceutical formulations containing a compound ofFormula I, such as those prepared in accordance with Example 1.

EXAMPLE 7

[0294] Hard gelatin capsules containing the following ingredients areprepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch305.0 Magnesium stearate 5.0

[0295] The above ingredients are mixed and filled into hard gelatincapsules.

EXAMPLE 8

[0296] A tablet formula is prepared using the ingredients below:Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[0297] The components are blended and compressed to form tablets.

EXAMPLE 9

[0298] A dry powder inhaler formulation is prepared containing thefollowing components: Ingredient Weight % Active Ingredient 5 Lactose 95

[0299] The active ingredient is mixed with the lactose and the mixtureis added to a dry powder inhaling appliance.

EXAMPLE 10

[0300] Tablets, each containing 30 mg of active ingredient, are preparedas follows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mgStarch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

[0301] The active ingredient, starch and cellulose are passed through aNo. 20 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 11

[0302] Suppositories, each containing 25 mg of active ingredient aremade as follows: Ingredient Amount Active Ingredient   25 mg Saturatedfatty acid glycerides to 2,000 mg

[0303] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 12

[0304] Suspensions, each containing 50 mg of active ingredient per 5.0mL dose are made as follows: Ingredient Amount Active Ingredient 50.0 mgXanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystallinecellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavorand Color q.v. Purified water to 5.0 mL

[0305] The active ingredient, sucrose and xanthan gum are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of the microcrystalline cellulose and sodiumcarboxymethyl cellulose in water. The sodium benzoate, flavor, and colorare diluted with some of the water and added with stirring. Sufficientwater is then added to produce the required volume.

EXAMPLE 13

[0306] A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 14

[0307] An injectable preparation is prepared having the followingcomposition: Ingredients Amount Active ingredient 2.0 mg/ml Mannitol,USP  50 mg/ml Gluconic acid, USP q.s. (pH 5-6) water (distilled,sterile) q.s. to 1.0 ml Nitrogen Gas, NF q.s.

EXAMPLE 15

[0308] A topical preparation is prepared having the followingcomposition: Ingredients grams Active ingredient 0.2-10 Span 60 2.0Tween 60 2.0 Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

[0309] All of the above ingredients, except water, are combined andheated to 60⁾ C with stirring. A sufficient quantity of water at 60⁾ Cis then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. 100 g.

EXAMPLE 16

[0310] Sustained Release Composition Weight Preferred Ingredient Range(%) Range (%) Most Preferred Active ingredient 50-95 70-90 75Microcrystalline cellulose (filler)  1-35  5-15 10.6 Methacrylic acidcopolymer  1-35   5-12.5 10.0 Sodium hydroxide 0.1-1.0 0.2-0.6 0.4Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0 Magnesium stearate 0.5-5.01-3 2.0

[0311] The sustained release formulations of this invention are preparedas follows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

[0312] The resulting tablets may be coated with an optional film-formingagent, for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropyl,methylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Rohm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

[0313] The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

[0314] In order to influence the dissolution rate, the time during whichthe compound containing powder is wet mixed is controlled. Preferablythe total powder mix time, i.e. the time during which the powder isexposed to sodium hydroxide solution, will range from 1 to 10 minutesand preferably from 2 to 5 minutes. Following granulation, the particlesare removed from the granulator and placed in a fluid bed dryer fordrying at about 60° C.

Abbreviations

[0315] Gpp(NH)p: 5′-guanylyl-imididodiphosphate

[0316] R-PIA: phenylisopropyladenosine

[0317] TEM buffer: Buffer containing 50 mM Tris, 1 mM EDTA and 1 0 mMMgCl₂

Reagents

[0318] Adenosine deaminase is purchased from Boehringer MannheimBiochemicals Indianapolis, Ind.). R-PIA, DMSO and rolipram are obtainedfrom Sigma-RBI (Natick, Mass.).

EXAMPLE 18

[0319] Stable transfection of HEK-293 or CHO cells. The cDNAs for humanA₁, A_(2A), A_(2B) or A₃ adenosine receptors (AdoRs) were prepared byRT-PCR from total RNAs of human cells or tissues and sequenced on bothstrands. The expression vector containing one of these cDNAs and asecond vector containing a neomycin or puromycin-resistance gene wereintroduced to HEK-293 or CHO cells by Lipofectin-Plus (Life Technology).Colonies were selected by growing transfected cells in the presence ofneomycin or puromycin. Stably transfected cells were maintained inDulbecco's modified Eagle's medium (DMEM) or F-12 medium with 10% fetalbovine serum, 100 μg/mL penicillin, 100 μg/mL streptomycin andappropriate concentrations of neomycin or puromycin. The HEK-A_(2A),HEK-A_(2B) and HEK-A₃ cells contain high densities of A_(2A), A_(2B) andA₃ AdoRs, respectively. CHO— A₁ and CHO— A₃ cells contain high densitiesof A₁ and A₃ AdoRs, respectively.

[0320] Membrane preparation. Monolayers of transfected cells were washedwith phosphate buffered saline (PBS) and harvested in a buffercontaining 10 mM HEPES (pH 7.4), 10 mM EDTA and protease inhibitors. Thecells were homogenized in polytron for 1 minute at setting 4 andcentrifuged at 29000 g for 15 minutes at 4° C. The cell pellets werewashed with a buffer containing 10 mM HEPES (pH7.4), 1 mM EDTA andprotease inhibitors, and were resuspended in the same buffersupplemented with 10% sucrose. Frozen aliquots were kept at −80° C.

[0321] Radioligand binding. The affinities of compounds for A₁, A_(2A),A_(2B) or A₃ AdoRs were determined in competition studies usingradioligands such as ³H—CPX (A₁ antagonist), or 3H—CCPA (A₁ agonist),³H-ZM 241385 (A_(2A) antagonist) or ³H-CGS 21680 (A_(2A) agonist), ³H-ZM241385 (A_(2B) antagonist) or ¹²⁵I-AB-MECA (A₃ agonist) and membranes ofcorresponding transfected cells. For example, to determine theaffinities for A₃ AdoRs, the competition assays were started by mixing0.2 nM ¹²⁵I-AB-MECA with various concentrations of test compounds and 25□g membrane proteins of HEK-A₃ or CHO-A₃ in TEM buffer (50 mM Tris, 1 mMEDTA and 10 mM MgCl₂) supplemented with 1 U/mL adenosine deaminase. Theassays were incubated for 90 minutes, stopped by filtration onto GF/Bfilter plates using Packard Harvester and washed four times withice-cold TM buffer (10 mM Tris, 1 mM Mg Cl₂, pH 7.4). The amounts ofradioligands that bound to the GF/B filter plates were determined byscintillation counting. Nonspecific binding was determined in thepresence of 10 μM R-PIA or 1 μM IB-MECA. B_(max) and K_(D) values werecalculated using GraphPad software.

EXAMPLE 19

[0322] [³⁵S]GTPγS Binding Assays

[0323] The ability of the adenosine A₃-agonists to stimulate [35 S]GTPγS binding is determined by a modification of the method described byLorenzen et al. (1996 Mol. Pharmacol. 49:915). Briefly, membranesisolated from transfected CHO cells (30-50 μg) are incubated in a volumeof 0.1 mL containing 50 mM Tris-HCl buffer pH 7.4, 5 mM MgCl₂, 100 mMNaCl, 1 mM dithiothreitol, 0.2 units mL⁻¹ adenosine deaminase, 0.5% BSA,1 mM EDTA, various concentrations of GDP and ³⁵S-GTPγS. Variousconcentrations of the putative A₃ agonists are added and the cellsincubated for 5-90 min at 30° C. Nonspecific binding is determined bythe addition of high concentrations of GTPγS to some of the membranesuspensions. At the end of the incubation, each suspension is filteredand the retained radioactivity determined as described above.

EXAMPLE 20

[0324] cAMP measurements. CHO-A₃ or HEK-A₃ cells were collected in PBScontaining 5 mM EDTA, washed with DMEM and resuspended in DMEMcontaining adenosine deaminase (1 unit/mL) at a density of100,000-1,000,000 cells/mL. The cells were kept at room temperature for0.5-1 hour before the experiments. To start the cAMP measurement, thecell suspension (100 μL) was mixed with 25 μL of test agents and thereaction was kept at 37° C. for 5-30 minutes. The reaction was stoppedby addition of 0.2N HCl (125 μL). Cell lysates were centrifuged for 10minutes at 1000 rpm. The supernatant (100 μL) was collected andacetylated. The concentrations of cAMP in the supernatants were measuredusing the direct cAMP assay according to the manufacturer's instructions(Assay Design). Alternatively, cells were harvested using 0.0025%trypsin and 2 mM EDTA in PBS, washed and resuspended in phenol-free DMEMto a concentration of 1×10⁶ cells/mL, and then incubated with 1 U/mL ofadenosine deaminase for 30 minutes at room temperature. In some case, afinal concentration of 50 μM of the phosphodiesterase IV inhibitor,rolipram, was added to the cells immediately prior to addition ofadenosine receptor agonists, antagonists, and forskolin. Afterincubating for 5-30 minutes at 37° C., cells were lysed and cAMPconcentrations were determined using cAMP-Screen Direct™ System (AppliedBiosystem) according to the manufacturer's instructions.

[0325] The compounds of Formula I were shown to be potent A₃ adenosinereceptor agonists in these assays.

[0326] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. All patents and publications cited above arehereby incorporated by reference.

What is claimed is:
 1. A compound of the formula:

wherein: R¹ is optionally substituted lower alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; X is a covalent bond or optionally substitutedalkylene; R² is R-Z-Y—C≡C— or optionally substituted pyrazolyl: in whichY is optionally substituted alkylene, Z is oxygen, sulfur or —NH—, andR⁴ is optionally substituted aryl or optionally substituted heteroaryl;and R³ is hydroxymethyl or —C(O)—NR⁵R⁶; in which R⁵ and R⁶ areindependently hydrogen or lower alkyl.
 2. The compound of claim 1,wherein R² is optionally substituted pyrazol-1-yl.
 3. The compound ofclaim 2, wherein R¹ is optionally substituted alkyl or optionallysubstituted aryl and R³ is hydroxymethyl.
 4. The compound of claim 3,wherein R² is pyrazo-1-yl substituted by optionally substituted loweralkyl, ester, aminocarbonyl, optionally substituted aryl, or optionallysubstituted heteroaryl.
 5. The compound of claim 4, wherein pyrazol-1-ylis substituted by optionally substituted phenyl or optionallysubstituted benzyl.
 6. The compound of claim 5, wherein R¹ is optionallysubstituted lower alkyl and X is a covalent bond.
 7. The compound ofclaim 6, wherein R¹ is methyl and R² is 4-(4-methoxyphenyl)pyrazol-1-yl,namely(4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol.8. The compound of claim 6, wherein R¹ is n-propyl and R² is4-(4-methoxyphenyl)pyrazol-1-yl, namely(4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol.9. The compound of claim 6, wherein R¹ is methyl and R² is4-(4-chlorobenzylaminocarbonyl)pyrazol-1-yl, namely(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl}pyrazol-4-yl)-N-(4-chlorophenyl)carboxamide.10. The compound of claim 6, wherein R¹ is methyl and R² is4-(4-chlorobenzylaminocarbonyl)pyrazol-1-yl, namely(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl}pyrazol-4-yl)-N-(4-chlorophenyl)carboxamide.11. The compound of claim 4, wherein R² is pyrazo-1-yl substituted byoptionally substituted heteroaryl.
 12. The compound of claim 11, whereinR¹ is n-propyl and R² is 4-(pyrid-2-yl)pyrazol-1-yl, namely(4S,2R,3R,5R)-5-(hydroxymethyl)-2-[4-(pyridin-2-yl)pyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol.13. The compound of claim 5, wherein R¹ is optionally substituted aryland X is alkylene.
 14. The compound of claim 13, wherein R¹ is3-iodobenzyl and R² is 4-(4-methoxyphenyl)pyrazol-1-yl, namely(4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[4-(4-methoxyphenyl)pyrazolyl]-6-(3-iodobenzylamino)purin-9-yl}oxolane-3,4-diol.15. The compound of claim 1, wherein R² is optionally substitutedpyrazol-4-yl.
 16. The compound of claim 15, wherein R¹ is optionallysubstituted alkyl or optionally substituted aryl, R³ is hydroxymethyl,and X is a covalent bond.
 17. The compound of claim 16, wherein R¹ ismethyl, R² is 1-benzylpyrazol-4-yl, R³ is hydroxymethyl, and X is acovalent bond, namely(4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[1-benzylpyrazolyl]-6-(methylamino)purin-9-yl}oxolane-3,4-diol.18. The compound of claim 16, wherein R¹ is n-propyll, R² is1-benzylpyrazol-4-yl, R³ is hydroxymethyl, and X is a covalent bond,namely(4S,2R,3R,5R)-5-(hydroxymethyl)-2-{2-[1-benzylpyrazolyl]-6-(n-propylamino)purin-9-yl}oxolane-3,4-diol.19. The compound of claim 1, wherein R² is R⁴-Z-Y—C≡C—.
 20. The compoundof claim 19, wherein R⁴ is optionally substituted phenyl and Y isalkylene of 1-3 carbon atoms.
 21. The compound of claim 20, wherein R⁴is phenyl optionally substituted by methoxy or chloro, and Y ismethylene.
 22. The compound of claim 21, wherein R¹ is optionallysubstituted alkyl, X is a covalent bond, and R³ is hydroxymethyl. 23.The compound of claim 22, wherein R¹ is methyl, R⁴ is phenyl and Z isoxygen, namely2-hydroxymethyl-5-[6-methylamino-2-(3-phenoxypropyn-1-yl)purin-9-yl]-tetrahydrofuran-3,4-diol.24. A method of treating a disease state in a mammal that is alleviableby treatment with a A₃ adenosine receptor agonist, comprisingadministering to a mammal in need thereof a therapeutically effectivedose of a compound of claim
 1. 25. The method of claim 24, wherein thedisease state is cancer.
 26. The method of claim 24, wherein the diseasestate is neutropenia.
 27. A pharmaceutical composition comprising atleast one pharmaceutically acceptable excipient and a therapeuticallyeffective amount of a compound of claim
 1. 28. A process for thepreparation of a compound of Formula I:

in which R² is optionally substituted pyrazol-1-yl; comprising:contacting a compound of the formula:

with a compound of formula:


29. The process of claim 28, wherein the reaction is conducted in aninert solvent chosen from methanol, ethanol, n-propanol, isopropanol,and t-butanol.
 30. A process for the preparation of a compound ofFormula I:

in which R² is optionally substituted pyrazol-4-yl; comprisingcontacting a compound of the formula:

with a compound of the formula:

in the presence of a palladium complex and a copper salt in an inertsolvent, and contacting the product with a mild acid.
 31. The process ofclaim 30, wherein the palladium complex is Pd(PPh₃)₄, the copper salt isCuI, the inert solvent is N,N-dimethylformamide, and the mild acid isammonium fluoride.
 32. A process for the preparation of a compound ofclaim 1, in which R² is R⁴-Z-Y—C≡C—; comprising: contacting in an inertsolvent a compound of the formula:

with a compound of the formula:

in the presence of a mild base, a copper salt and a palladium catalyst.33. The process of claim 32, wherein the inert solvent isN,N-dimethylformamide, the base is triethylamine, the copper salt iscopper iodide, and the palladium catalyst isdichlorobis-(triphenylphosphine)palladium(II).